A new strategy to cure diseases in one day and forever: epigenetic silencing

A team of Italian researchers has achieved a scientific milestone that heralds a revolution in medicine.

The authors have managed to silence a gene associated with high cholesterol levels, without having to modify the DNA.

The work, carried out in mice, shows that the effects persisted throughout the year that the experiment lasted, a period equivalent to half a human life.

These results suggest that it is possible to solve chronic health problems in a single day and forever.

The study is published this Wednesday in the journal

, the flagship of the best world science.

DNA is a book of 3 billion chemical letters, with the instructions for the functioning of each cell.

This immense text is divided into pages—the genes—with specific recipes to make the proteins necessary for life: the collagen in cartilage, the hemoglobin in the blood, the antibodies that fight pathogens.

One of these genes,

, contains the guidelines for producing a protein associated with high levels of bad cholesterol.

The American company Verve Therapeutics announced on November 12 that it had edited the DNA of the liver cells of a dozen people with dangerous congenital hypercholesterolemia, inactivating their

gene and managing to reduce cholesterol by half.

This experimental therapy, called VERVE-101, was the first to use the revolutionary CRISPR gene editing tools to modify DNA directly in a patient, not in cells in the laboratory.

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The new study has achieved something similar, but without altering the DNA.

The Italian team, led by biotechnologist Angelo Lombardo, has not made genetic changes, but rather epigenetic ones.

If DNA is interpreted as words with instructions, epigenetic modifications are like chemical accents, with the capacity to alter the message.

Lombardo's group has silenced this bad cholesterol gene by adding small molecules to the DNA of liver cells.

“It is the first published demonstration that a single treatment with epigenetic editors can produce stable silencing of a gene,” celebrates the Italian scientist, from the San Raffaele Telethon Institute of Gene Therapy, in Milan.

Lombardo proclaims that “there are many diseases that can be treated with epigenetic editing.”

The researcher mentions other liver pathologies, such as hepatitis B, caused by a virus that embeds its genetic material in the human cell.

“In terms of cancer, we ourselves and other groups are using epigenetic editing to silence multiple genes in T lymphocytes [white blood cells that defend the human body], with the aim of making these cells better fight tumors,” he adds. Lombard.

The Italian biotechnologist and other American colleagues created a company, Chroma Medicine, in 2021 to “revolutionize the treatment of diseases” through epigenetic editing.

The company, with headquarters in Boston and Milan, was born with around 115 million euros in financing.

Among its co-founders is chemist David Liu, a Harvard University researcher who has transformed medicine with his CRISPR genetic engineering tools, such as base editors, a kind of pencil with an eraser, capable of eliminating a single letter. of DNA and replace it with another.

The company Verve Therapeutics has used these sophisticated base editors to inactivate the bad cholesterol gene in its initial dozen patients.

Angelo Lombardo argues that epigenetic editing has advantages over DNA modification.

“It does not induce breaks in the genome, which can be toxic, and it can also be reversed with drugs or other epigenetic editing strategies that reactivate the silenced gene.

So you have possible antidotes in case of adverse effects,” he argues.

The Italian biotechnologist emphasizes that it is an experimental therapy that has yet to confirm its immense potential in other animal tests, possibly in monkeys, but he believes that clinical trials in humans “will not take long.”

Epigenetics expert Manel Esteller applauds the new work, in which he has not participated.

“The curious thing about the case is that it seems that these modifications are maintained over time and are even preserved when the liver cells divide.

The mechanisms of this persistence are not clear, but, if the study is validated in other animal models and transferred to humans, it could mean that it would be enough to simply treat a defect or excess of a gene with one dose," analyzes Esteller, director of the Josep Carreras Leukemia Research Institute, in the Barcelona town of Badalona.

The scientist explains that, currently, there are nine epigenetic drugs approved for use in oncology, especially in leukemias, lymphomas and soft tissue tumors.

A month ago, Esteller's team discovered “the factors that predict whether epigenetic treatment will be effective or not in a patient.”

A year ago, Spanish biologist heart.

Menéndez Caravia states that “epigenetic silencing is an original and novel idea,” but he would not have been able to replace the precision of the genetic pencil in his experiment.

silencing

, that is, the unwanted repression of genes that are not

.

silencing

of several genes whose consequences are unknown.

The repercussions that this would have on liver cells should be explored in depth,” warns the biologist.

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